Iterative Modeling Reveals Evidence of Sequential Transcriptional Control Mechanisms.
Iterative Modeling Reveals Evidence of Sequential Transcriptional Control Mechanisms.
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DOI：
10.1016/j.cels.2017.01.012
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发表时间：
2017-03-22
期刊：
影响因子：
9.3
通讯作者：
Hoffmann A
中科院分区：
文献类型：
--
作者：
Cheng CS;Behar MS;Suryawanshi GW;Feldman KE;Spreafico R;Hoffmann A
基因表达的组合控制被认为是由同源转录因子（TFs）之间的分子相互作用介导的。虽然关于tf全基因组位置的信息是可用的，但它们调节的基因以及它们是否组合起作用通常仍然是一个悬而未决的问题。在这里，我们开发了一种机械的，而不是统计的建模方法来阐明基因表达数据中的TF控制逻辑。将这种方法应用于85个数据集中的数百个基因，测量小鼠成纤维细胞和巨噬细胞对细胞因子和病原体的转录反应，我们发现刺激反应性tf通常在逻辑OR门或单个门中依次起作用。在nfκ b响应的mRNA合成和mapkp38响应的mRNA半衰期控制之间存在逻辑与门，但在时间上一致的tf之间没有。我们的分析确定了每个病原体应答tf的功能靶基因，并促使对基因表达组合控制的概念基础进行修订，包括控制mRNA合成和衰变的顺序作用分子机制。迭代系统建模方法揭示了小鼠成纤维细胞和巨噬细胞的病原体应答转录组如何通过核转录因子和细胞质mRNA半衰期调节因子的组合来指定。
Combinatorial control of gene expression is presumed to be mediated by molecular interactions between coincident transcription factors (TFs). While information on the genome-wide locations of TFs is available, the genes they regulate and whether they function combinatorially often remain open questions. Here, we developed a mechanistic, rather than statistical, modeling approach to elucidate TF control logic from gene expression data. Applying this approach to hundreds of genes in 85 datasets measuring the transcriptional responses of murine fibroblasts and macrophages to cytokines and pathogens, we found that stimulus-responsive TFs generally function sequentially in logical OR gates or singly. Logical AND gates were found between NFκB-responsive mRNA synthesis and MAPKp38-responsive control of mRNA half-life, but not between temporally coincident TFs. Our analyses identified the functional target genes of each of the pathogen-responsive TFs and prompts a revision of the conceptual underpinnings of combinatorial control of gene expression to include sequentially acting molecular mechanisms that govern mRNA synthesis and decay. An iterative systems modeling approach reveals how the pathogen-responsive transcriptome of murine fibroblasts and macrophages is specified by combinations of nuclear transcription factors and cytoplasmic mRNA half-life regulators.